2-Decarboxy-2-hydroxymethyl-6-alkoxy-PGI1 compounds

ABSTRACT

Prostacyclin I 1 , (PGI 1 ) derivatives and analogs having a 6-alkoxy feature and having pharmacological activity and processes for preparing them are disclosed.

DESCRIPTION CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of Ser. No. 892,108, filedMar. 31, 1978, now pending.

BACKGROUND OF THE INVENTION

The present invention relates to novel2-decarboxy-2-hydroxymethyl-6-alkoxy-PGI₁ compounds, useful aspharmaceutical agents, principally for the induction of certainprostacyclin-like pharmacological effects. The essential materialconsisting of description of the preparation and use of these substancesis incorporated here by reference from Ser. No. 892,108, filed Mar. 31,1978, now pending.

SUMMARY OF THE INVENTION

The present invention particularly relates to a compound of formula 1##STR1## wherein L is (1) --(CH₂)_(d) --C(R₂)₂ --,

(2) --CH₂ --O--CH₂ --Y--, or

(3) --CH₂ CH═CH--,

wherein d is zero to 5, R₂ is hydrogen, methyl or fluoro, being the sameor different with the proviso that one R₂ is not methyl when the otheris fluoro, and Y is a valence bond, --CH₂ --, or --(CH₂)₂ --;

wherein Q is oxo, α--H:β--H, α--R₈ :β--OH, or α--OH:β--R₈,

wherein R₈ is hydrogen or alkyl of one to 4 carbon atoms, inclusive;

wherein R₄ is

(1) --C(R₅)(R₆)--C_(g) H_(2g) --CH₃,

(2) --C(R₅)(R₆)--Z--(Ph), or

(3) cis--CH₂ --CH═CH--CH₂ CH₃,

wherein C_(g) H_(2g) is alkylene of one to 9 carbon atoms, inclusive,with one to 5 carbon atoms, inclusive, in the chain between --CR₅ R₆ --and terminal methyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4carbon atoms, inclusive, or fluoro, being the same or different, withthe proviso that one of R₅ and R₆ is fluoro only when the other ishydrogen or fluoro and the further proviso that neither R₅ nor R₆ isfluoro when Z is oxa (--O--); wherein Z represents an oxa atom (--O--)or C_(j) H_(2j) wherein C_(j) H_(2j) is a valence bond or alkylene ofone to 9 carbon atoms, inclusive, with one to 6 carbon atoms, inclusivebetween CR₅ R₆ -- and the (Ph);

wherein (Ph) is phenyl or phenyl substituent by (T)s,

wherein T is alkyl of one to 4 carbon atoms; inclusive, fluoro, chloro,trifluoromethyl, or --OR₇ wherein R₇ is alkyl of one to 4 carbon atoms,inclusive, and s is zero, one, 2 or 3, with the proviso that not morethan two T's are other than alkyl and when s is 2 or 3 the T's areeither the same or different;

wherein W₁ is α--OH:β--H, α--H:β--OH, oxo, methylene, α--H:β--H, orα--CH₂ OH:β--H;

wherein R₆₀ is straight-chain alkyl of one to 6 carbon atoms, inclusive;and

wherein X is

(1) trans--CH═CH--,

(2) cis--CH═CH--,

(3) --C.tbd.C--, or

(4) --CH₂ CH₂ --.

With regard to the divalent substituents described above, e.g., Q andW₁, these divalent radicals are defined as α--R_(i) :β--R_(j) whereR_(i) represents a substituent of the divalent moiety of the alphaconfiguration with respect to the cyclopentane ring and R_(j) representsa substituent of the divalent moiety of the beta configuration withrespect to the cyclopentane ring. Accordingly, when Q is defined asα--OH:β--R₈, the hydroxy of the alpha moiety is in the alphaconfiguration, i.e. as in prostacyclin, and the R₈ substituent is in thebeta configuration. Not all carbon atoms to which such divalent moietiesare attached represent asymmetric centers. For example, when bothvalence bonds are to hydrogen, (e.g., W₁ or Q is α--H:β--H), then noasymmetric center is present.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention particularly relates to the following chemicalcompound:

2-Decarboxy-2-hydroxymethyl-9-deoxy-6ξ,9α-epoxy-6ξ-methoxy-PGF.sub.1.

I claim:
 1. A compound of the formula ##STR2## wherein L is (1)--(CH₂)_(d) --C(R₂)₂ --(2) --CH₂ --O--CH₂ --Y-- or (3) --CH₂ CH═CH--wherein d is zero to 5, R₂ is hydrogen, methyl or fluoro, being the sameor different with the proviso that one R₂ is not methyl when the otheris fluoro, and Y is a valence bond, --CH₂ --, or --(CH₂)₂ --; wherein Qis oxo, α--H:β--H, α--R₈ :β--OH, or α--OH:β--R₈, wherein R₈ is hydrogenor alkyl of one to 4 carbon atoms, inclusive; wherein R₄ is(1)--C(R₅)(R₆)--C_(g) H_(2g) --CH₃ (2) --C(R₅)(R₆)--Z--(Ph) or (3) cis--CH₂--CH═CH--CH₂ CH₃, wherein C_(g) H_(2g) is alkylene of one to 9 carbonatoms, inclusive, with one to 5 carbon atoms, inclusive, in the chainbetween --CR₅ R₆ -- and terminal methyl, wherein R₅ and R₆ are hydrogen,alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same ordifferent, with the proviso that one of R₅ and R₆ is fluoro only whenthe other is hydrogen or fluoro and the further proviso that neither R₅nor R₆ is fluoro when Z is oxa (--O--); wherein Z represents an oxa atom(--O--) or C_(j) H_(2j) wherein C_(j) H_(2j) is a valence bond oralkylene of one to 9 carbon atoms, inclusive, with one to 6 carbonatoms, inclusive between CR₅ R₆ -- and the (Ph) ring; wherein (Ph) isphenyl or phenyl substituent by (T)s, wherein T is alkyl of one to 4carbon atoms; inclusive, fluoro, chloro, trifluoromethyl, or --OR₇wherein R₇ is alkyl of one to 4 carbon atoms, inclusive, and s is zero,one, 2 or 3, with the proviso that not more than two T's are other thanalkyl and when s is 2 or 3 the T's are either the same or different;wherein W₁ is α--OH:β--H, α--H:β--OH, oxo, methylene, α--H:β--H, orα--CH₂ OH:β--H; wherein R₆₀ is straight-chain alkyl of one to 60 carbonatoms, inclusive; and wherein X is(1) trans--CH═CH--, (2) cis--CH═CH--,(3) --CH.tbd.CH--, or (4) --CH₂ CH₂ --.
 2. A compound according to claim1 wherein W₁ is α--OH:β--H and L is --(CH₂)₃ --.
 3. A compound accordingto claim 2 wherein X is trans--CH═CH--.
 4. A compound according to claim3 wherein Q is α--OH:β--H.
 5. A compound according to claim 4 wherein R₄is --C(R₅)(R₆)--C_(g) H_(2g) --CH₃.
 6. A compound according to claim 5wherein R₅ and R₆ are hydrogen and C_(g) H_(2g) is --(CH₂)₃ --. 7.2-Decarboxy-2-hydroxymethyl-9-deoxy-6ξ,9.alpha.-epoxy-6ξ-methoxy-PGF₁, acompound according to claim
 6. 8. A compound according to claim 4wherein R₄ is benzyl.
 9. A compound according to claim 2 wherein X is--CH₂ CH₂.
 10. A compound according to claim 1 wherein W₁ is α--H:β--Hand L is --(CH₂)₃ --.